Summary of Work: The glucocorticoid hormone action group studies how environmental stressors elicit and transmit metabolic signals. Our primary interest is in glucorticoid receptor signaling, adaptation to chronic environmental stress, and resistance to glucocorticoids. Recent studies have shown that a mutual antagonism exists between pro- inflammatory cytokine and glucocorticoid signaling. Specifically, signal transduction by the glucocorticoid receptor is impaired in cells with active nuclear NFkB, and signal transduction by NFkB is impaired in cells when the glucocorticoid receptor is active. We are studying the mechanism of this antagonism at the level of protein/protein interactions. A second effort is aimed at understanding what role phosphorylation has in glucocorticoid receptor signal transduction. Glucocorticoid receptors are phosphoproteins, but very little information is available on howphosphorylation affects receptor function. Interestingly, glucocorticoid receptor phosphorylation modulates receptor transcriptional activation but not repression. Furthermore receptor phosphorylation controls the half life of the protein. Another focus of our work is on glucocorticoid receptor down regulation which leads to resistance to steroids. We have shown that the glucocorticoid receptor represses the expression of its own gene. This repression occurs via a consequence of the direct interaction of the glucocorticoid receptor with two novel intragenic binding sites within the gene. Mutational analyses of these sites are being performed. Finally, we have recently described the widespread expression of a second form of human glucocorticoid receptor. This receptor, termed hGRBeta, is an alternatively spliced product from the same gene and functions as a strong dominant negative inhibitor of glucocorticoid receptor signalling. This receptor shows strong expression in epithelia cells and appears to be overexpressed in steroid resistant asthma. - Glucocorticoid Receptors, Transcription, Streroid Resistence